Active specific immunotherapy with polyvalent melanoma cell vaccine for patients with in-transit melanoma metastases

Hsueh, Eddy C.; Nathanson, Larry; Foshag, Leland J.; Essner, Richard; Nizze, J. Anne; Stern, Stacey L.; Morton, Donald L.

doi:10.1002/(sici)1097-0142(19990515)85:10<2160::aid-cncr10>3.0.co;2-0

Cited by 59 publications

(19 citation statements)

References 20 publications

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“…However, it is apparent that responses induced by the various vaccines commonly last for 6 months and several of the studies report at least 1 or 2 long-term survivors. 21,28,29 In our study, the median response duration was 10 months and the most durable response continues for more than 47 months. The effect of vaccine-induced tumor regression on survival is generally ignored, perhaps because the small sample sizes render difficult the demonstration of statistically significant differences between responders and nonresponders.…”

Section: Discussionmentioning

confidence: 48%

“…McCune et al 20 applied the autologous cell approach to adenocarcinoma of the kidney; 4/14 patients with measurable metastases responded. Allogeneic vaccines can apparently induce tumor regression as well: in a recent report of the vaccine developed by Morton, Hsueh et al 21 described regression of cutaneous in-transit metastases in 9/54 patients following administration of a vaccine comprising a pool of irradiated, melanoma cell lines. Mitchell et al 22 observed tumor regression in 4/25 patients treated with Melacine , a preparation of lysates derived from melanoma cell cultures mixed with the adjuvant DETOX.…”

Section: Discussionmentioning

confidence: 99%

“…18,21,22,28 Even more remarkable was the kinetics of the tumor regression. Significant tumor shrinkage required at least 4 -5 months and in 2 of these cases maximum regression was not observed for 1 year.…”

Section: Discussionmentioning

confidence: 99%

“…The effect of vaccine-induced tumor regression on survival is generally ignored, perhaps because the small sample sizes render difficult the demonstration of statistically significant differences between responders and nonresponders. In 1 study that included survival analysis, 21 clinical response to vaccine produced no survival benefit: nonresponders who underwent excision of skin metastases lived as long as patients whose metastases regressed after vaccine administration. Our study, then, appears to be unique in its demonstration of prolonged survival of vaccine responders, even in a multivariate analysis Progress in human cancer immunology has been limited by the absence of a test that reliably determines whether or not a patient has developed a cell-mediated immune response to tumor-associated antigens.…”

Section: Discussionmentioning

confidence: 99%

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Treatment of metastatic melanoma with autologous, hapten‐modified melanoma vaccine: Regression of pulmonary metastases

et al. 2001

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Key words: melanoma; vaccine; immunotherapy; autologous; cyclophosphamideStudies performed and published over the past 30 years have made it clear that immunizing a tumor-bearing patient to his or her own tumor cells is exceedingly difficult. An appealing explanation for this difficulty is that tumor antigens are weakly immunogenic and often induce tolerance, i.e., paralysis of the immune response, rather than effective immunity. 1 Fortunately, advances in basic immunology have disclosed a number of ways of breaking immunologic tolerance. One way is the judicious use of cytotoxic drugs. In 1967, Maguire and Ettore 2 made the surprising discovery that administration of cyclophosphamide to animals prior to an immunization caused the cell-mediated immune response to be augmented rather than suppressed. We have shown that this phenomenon applies to cancer-bearing humans as well. Thus, the administration of low-dose (300 mg/m 2 ) cyclophosphamide prior to an immunization with autologous tumor cells greatly increased the development of cell-mediated immunity to those cells. 3 A second approach to circumventing tolerance is the use of haptens-small molecules that are incapable of inducing an immune response unless they are coupled to a larger molecule. Coupling of a hapten to a protein, i.e., hapten modification, often results in the induction of an immune response to the protein that would otherwise not be possible. For example, Weigle, 4 in a series of now classic experiments, immunized mice with hapten-modified thyroglobulin. This resulted in the induction of an immune response not only to the hapten-modified thyroglobulin, but also to unmodified, i.e., native, thyroglobulin and produced autoimmune thyroiditis. A similar phenomenon was observed more recently by Neurath et al. 5 They found that application of the hapten dinitrophenyl to the colonic mucosa of mice resulted in the development of an autoimmune colitis, similar to human ulcerative colitis. Initially, these mice developed cellular immunity to the haptenmodified mucosa. However, as the chemically modified mucosa cells were shed, a potent immune response to the normal, unmodified mucosa developed, which led to the autoimmune pathology.The immunologic basis of these interesting phenomena is now clear: there are T lymphocytes generated by immunization with hapten-modified cells that are reactive to both modified and unmodified cells. For example, class I MHC-restricted T-cell clones generated from mice immunized with TNP-modified syngeneic lymphocytes respond to MHC-associated, TNP-modified "self" peptides. Furthermore, some TNP-reactive clones respond to certain MHC-binding, unmodified peptides as well. 6 These observations in animal models provide a strong rationale for a human cancer vaccine consisting of autologous tumor cells modified with a hapten, DNP, preceded by the administration of low-dose cyclophosphamide. We have observed that administration of DNP vaccine to patients with metastatic melanoma induces a unique reaction-the development of inflamma...

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Section: Discussionmentioning

confidence: 48%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Treatment of metastatic melanoma with autologous, hapten‐modified melanoma vaccine: Regression of pulmonary metastases

et al. 2001

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“…Different approaches to improving the immune response to ganglioside vaccines in cancer patients have been conducted by several groups. Purified gangliosides attached to bacillus Calmette-Guérin or coupled to a carrier protein such as keyhole limpet hemocyanin and whole cell vaccines have been able to induce an Ab response in vaccinated patients (1)(2)(3).…”

mentioning

confidence: 99%

An Anti-Idiotype Vaccine Elicits a Specific Response to N-Glycolyl Sialic Acid Residues of Glycoconjugates in Melanoma Patients

Alfonso

Diaz

Hernández

et al. 2002

The Journal of Immunology

113

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We generated the 1E10 γ-type anti-idiotype mAb (Ab2) specific to an Ab1 mAb able to react specifically with N-glycolyl-containing gangliosides and with Ags expressed on human melanoma and breast carcinoma cells. This Ab2 mAb induced an Ab response in animal models sharing immunochemically defined idiotopes with the Ab1. The treatment of tumor-bearing mice with 1E10 mAb induced a strong antitumor activity. A clinical trial was conducted in 20 patients with advanced malignant melanoma. Patients were treated with six intradermal injections of aluminum hydroxide-precipitated 1E10 anti-Id mAb given at 2-wk intervals. Sixteen of the 17 patients who received at least four doses of the anti-Id vaccine develop Ab3 Abs capable of inhibiting Ab2 binding to Ab1 (Ab3Id+). In contrast to the incapacity of 1E10 mAb to generate Ab3 Abs with the same antigenic specificity as the Ab1 mAb in mice, a very specific and strong Ab3 response against N-glycolyl-containing gangliosides was induced in 16 patients (Ab3Ag+). No evidence of serious or unexpected adverse effects has been observed in this clinical trial. 1E10 anti-Id vaccine was safe, well tolerated, and immunologically effective, with most patients being able to generate a specific immune response against 1E10 and Neu-glycolyl-GM3 ganglioside.

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Risk reduction endpoints should be part of the design of adjuvant therapy clinical trials for patients with melanoma

Nathanson

2001

Cancer

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Active specific immunotherapy with polyvalent melanoma cell vaccine for patients with in-transit melanoma metastases

Cited by 59 publications

References 20 publications

Treatment of metastatic melanoma with autologous, hapten‐modified melanoma vaccine: Regression of pulmonary metastases

Treatment of metastatic melanoma with autologous, hapten‐modified melanoma vaccine: Regression of pulmonary metastases

An Anti-Idiotype Vaccine Elicits a Specific Response to N-Glycolyl Sialic Acid Residues of Glycoconjugates in Melanoma Patients

Risk reduction endpoints should be part of the design of adjuvant therapy clinical trials for patients with melanoma

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